581 Ixekizumab reduces key IL-17 and IL-23 pathway genes more rapidly than guselkumab: 4-week results from IXORA-R

Emerging evidence suggests that interleukin (IL)-17 and IL-23 may have distinct but overlapping roles in psoriasis-centric pathways, working in tandem to drive inflammation and epidermal hyperplasia. Here, we examined the effects of ixekizumab (IXE) and guselkumab (GUS) on IL-17/IL-23 pathway gene expression in psoriasis lesions at weeks 0, 1, 2, and 4 from patients enrolled in the IXORA-R trial. IXORA-R (NCT03573323) was a head-to-head trial of IXE vs GUS examining responses as early as week 1 in patients with moderate-to-severe plaque psoriasis. A subset of patients consented to have skin biopsies from lesions at weeks 0 (baseline), 1, 2, and 4. We assessed transcriptomic changes from baseline at each timepoint and assessed normalization of inflammatory gene signatures from key psoriasis-associated cytokines (eg, IL-17A, TNF, IFNA, IL-36) along with cell-type deconvolution using psoriasis single-cell RNA-seq data. Changes in transcriptomic signatures were further cross-correlated with clinical improvement (PASI). Patients on IXE had more rapid and significant shifts of inflammatory signatures towards normal compared to patients on GUS. Genes induced by IL-17A were shifted towards ∼70% normal (from baseline of 40%) by week 4 in the IXE group compared to ∼50% for GUS. This was accompanied by decreased epidermal layer signatures, which were significantly improved by week 1 in the IXE group vs week 2 in the GUS group. Epidermal IL-17A and IL-36 responses correlated with PASI 100 earlier for IXE vs GUS, with IL-17A-regulated genes demonstrating the most significant correlation (r=0.54; p=4.07x10-6) in the IXE group. In conclusion, IXE led to a more rapid normalization of the transcriptomic changes in psoriasis compared to GUS, with rapid suppression of IL-17 responses in psoriatic skin, correlating with clinical improvement.